The p90 ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases that are constituents of the AGC subfamily in the human kinome. Each of the 4 RSK isoforms are products of separate genes and are characterized by 75%-80% sequence identity. While the RSK isoforms are widely distributed among human tissues, their variable tissue expression patterns indicate that they may have distinct physiologic/pathologic roles. The RSK isoforms are activated by growth factors, cytokines, peptide hormones and neurotransmitters that stimulate the Ras-ERK pathway.
RSK regulates numerous biological processes through its phosphorylation of cellular substrates. One important cardiovascular target of RSK is the Na+/H+ exchanger isoform 1 (NHE1). RSK-mediated phosphorylation of NHE1 at S703 is responsible for increased NHE1 activity following Ang II stimulation, oxidative stress, and myocardial injury. NHE1 is a highly validated target for its role in both ischemia reperfusion (I/R) injury and congestive heart failure. Increased NHE1 activity correlates to the extent of myocardial damage following I/R, while NHE1 inhibitors administered in a prophylactic manner are capable of preserving cardiac function after I/R. Additionally, increased NHE1 activity is observed in isolated myocytes from failing human hearts and in animal models of hypertrophy suggesting chronic activation of this exchanger in cardiovascular pathologies. Despite robust pre-clinical data linking NHE1 activity to cardiovascular dysfunction, there are currently no approved NHE1 inhibitors on the market. Adverse events, such as headache, eye pain, and paresthesia, were reported in clinical trials, and it is hypothesized that these events are due to direct and complete NHE1 inhibition which impairs its physiological function of maintaining intracellular pH. Based on this safety concern, alternate approaches that do not inhibit basal NHE1 activity but regulate activity during periods of cardiovascular stress may offer an additional safety margin.
In cardiomyocytes RSK has been recognized as a predominant kinase that phosphorylates the c-terminal regulatory region of NHE1 and is required for NHE1 activation in response to I/R, oxidative stress, and receptor activation by Ang II and phenylephrine. Recent studies by Maekawa et al. (Naoya Maekawa, Jun-ichi Abe, Tetsuro Shishido, Seigo Itoh, Bo Ding, Virendra K. Sharma, Shey-Shing Sheu, Burns C. Blaxall and Bradford C. Berk Circulation 113:2516-2523, 2006) demonstrated that that RSK was rapidly activated in the heart tissue exposed to I/R. Furthermore, cardiomyocyte specific expression of dominant negative RSK prevented cardiomyocyte apoptosis and improved post MI remodeling and left ventricular function. Importantly, inhibition of RSK activity by means of overexpressing a dominant negative RSK protein decreased agonist-activated NHE1 function without affecting basal, homeostatic NHE1 function. Similarly, the RSK inhibitor, fmk, has been shown to inhibit phosphorylation of NHE1 and phenylephrine-induced enhanced NHE1 activity without affecting basal activity (Friederike Cuello, Andrew K. Snabaitis, Michael S. Cohen, Jack Taunton, and Metin Avkiran, Mol Pharmacol 71:799-806, 2007). These findings suggest that inhibition of RSK activity may be an alternative therapeutic strategy by which NHE1 activity can be differentially regulated, effectively preserving basal function and increasing the safety window.